The present invention relates to new arylaminoalcohol derivatives of formula (I) and to a method for the preparation of such compounds. The invention also relates to the use of these compounds as medicaments, and in particular for the prevention and/or the treatment of parasitic diseases caused by apicomplexan parasites such as malaria and toxoplasmosis. Finally, the invention relates to pharmaceutical compositions containing such compounds of formula (I) as active principles.
According to the World Health Organization (World malaria report 2011, http://www.who.int/malaria/world_malaria report_2011/es/index.html), malaria is endemic in 106 countries, affecting more than 200 million people and killing approximately 600.000 people every year, 90% of which are children. Malaria control programs relying on disease prevention and artemisinin-based combination therapies (ACT) have been extremely effective in reducing the disease burden, resulting in a 25% decline in malaria death rates in the last decade, with the highest impact in European countries (99%) while traditionally highly endemic countries of African and American regions report decrease of 33 and 42% respectively. Unfortunately, the emergence of resistance to current treatments and today's global economic situation require a search for new, effective and inexpensive molecules.
Arylaminoalcohols are an important group of compounds with known antimalarial activity and they have been used as antimalarial agents since the 70's. Hydroxylpropyl-piperazine derivatives, belonging to this chemical family, have shown outstanding activity against of Plasmodium falciparum chloroquine-resistant strains (A. Mendoza et al., Exp. Parasit. 128(2) (2011) 97-103). According to recent publications (W. Cunico et al., Eur. J. Med. Chem 44 (2009) 1363-1368; W. Cunico et al., Eur. J. Med. Chem 44 (2009) 3816-3820), piperazine derivatives could target Plasmodium plasmepsin II enzyme. This enzyme, that recently caused much interest, is involved in the initial steps of the hemoglobin degradation (R. Bruckner, Advanced organic chemistry: reaction mechanisms, Harcout/Academic Press: San Diego, (2002), pp. 636), which is a critical issue in the intra-erythrocytic cycle of the parasite, taking place inside the food vacuole.
Given the small number of available medicaments and the resistance they have already induced, discovery of new targets and of new medicaments remains a key priority. In an effort to discover such new compounds, the Inventors have surprisingly discovered a new class of arylaminoalcohol derivatives of formula (I) showing greater antiplasmodial activity than known arylaminoalcohols. Some of the arylaminoalcohols of the invention inhibit up to 50% of the growth of Plasmodium falciparum chloroquine-resistant FCR-3 strain in culture at dose <0.5 Moreover, the arylaminoalcohol derivatives of the invention are active in vivo in murine model.